Sara Clasen is the 2023 winner of the NOSTER & Science Microbiome Prize for her work in illuminating how so-called "silent flagellins" from beneficial microbiota evade a person's innate immunity.
The flagellins are microbial proteins that act as ligands, or molecules that the immune system uses to identify an invading pathogen. When ligands interact and bind with host immune receptors, they can trigger an immune response.
However, ligands aren't only produced by would-be pathogenic microbes — many are also produced by trillions of microbes that inhabit the gut microbiome, the vast majority of which are nonpathogenic and beneficial to human health.
How innate immune receptors tolerate ligands from beneficial microbes while recognizing those from pathogens remains poorly understood.
The discovery of silent flagellins offers new insights into one way innate immune receptors tolerate common or conserved ligands from commensal microbes that inhabit the human body.
"Once again in 2023 the NOSTER & Science Microbiome Prize has attracted a stellar lineup of candidates," said Caroline Ash, senior editor at Science. "I am delighted we can recognize and promote the contributions of three outstanding young scientists."
Clasen's prize-winning essay was published in the July 7 issue of Science.
Discovering Silent Flagellins
To address this question of tolerance, Clasen and her laboratory focused on the response of Toll-like receptor 5 (TLR5) to flagellin ligands. TLR5 receptors are located primarily in the plasma membrane of various immune and non-immune cells, where they interact with specific ligands derived from pathogens or damaged host cells.
Both invading pathogenic microbes and the beneficial commensal bacteria that inhabit our bodies produce flagellins — a crucial protein used to build the filaments used for microbial locomotion.
When these flagellar filaments of pathogens break down, their constituent flagellins bind to TLR5, which initiates an immune response. This response is well characterized for pathogens like Salmonella but not well-understood for flagellins from commensal bacteria.
"In the literature, flagellin is often used as shorthand for the Salmonella flagellin, FliC. But flagellins are amazingly diverse," said Clasen. "There are over 5,000 different flagellins produced by human gut microbiota."
In their study, Clasen and her team identified and characterized the interactions between TLR5 and 40 flagellins that are abundant in the human microbiome and discovered so-called silent flagellins, which strongly bind but weakly activate TLR5.
"When we screened flagellins for their ability to bind and activate TLR5, we expected weak binders to be weak activators and strong binders to be strong activators," said Clasen. "To our surprise, we discovered a third group: strong binders that induce weak activity."
According to the findings, unlike pathogen-derived flagellins, these silent flagellins produced by beneficial microbes lack a secondary TLR5 binding site, which mediates their immune receptor response.
Although Clasen and the researchers revealed that silent flagellins are ubiquitous throughout the human microbiome, they note that their levels appear to be substantially lower in populations from industrialized regions. Why this is remains poorly understood and a target for future research, but Clasen suggests that the findings could help explain the increased incidences of inflammatory disease, such as inflammatory bowel disease, in these populations.
"Overactivation of TLR5 is a feature of several inflammatory disorders, but the receptor is not druggable at the moment," said Clasen. "If we can figure out how TLR5 is turned on, we might be able to therapeutically manipulate it."
The NOSTER & Science Microbiome Prize aims to reward innovative research from young investigators working on the functional attributes of the microbiota of any organism that has potential to contribute to our understanding of health and disease, or to guide novel therapeutic interventions.
"This is the fourth year of the prize. I am delighted that once again this year's young scientists are passionately pursuing research on the development of microbiome-based therapeutics for the benefit of human health," said Kohey Kitao, CEO of NOSTER Inc. "I am excited to see that the prize is contributing to scientific discovery for the prevention and treatment of many chronic diseases globally."
Clasen, is currently a postdoctoral fellow in the department of microbiome science and the Max Planck Institute for Biology in Tübingen, Germany.
Christopher Stewart is a finalist for his essay "Diet-microbe-host interaction in early life: breastmilk bioactives are important to infant microbiome," which focused on the impact of human milk oligosaccharides in maternal milk on the developing infant gut microbiome. Stewart received graduate degrees and a Ph.D. from Northumbria University. After completing a postdoctoral fellowship at Baylor College of Medicine, Steward started his lab in the Translational and Clinical Research Institute at Newcastle University. His research is focused on microbial-host interaction in the gut of infants born premature.
Christoph Thaiss is a finalist for his essay "A microbiome exercise: gut-brain connections drive the motivation to work out," which focused on the microbiome's role in exercise performance and benefits. Thaiss received his undergraduate degrees from the University of Bonn, Yale University and ETH Zürich, and a Ph.D. from the Weizmann Institute of Science. After completing his doctoral training, Thaiss founded his lab in the Microbiology Department of the Perelman School of Medicine at the University of Pennsylvania, where his research focuses on the multifaceted interactions between environmental factors, the gut microbiome, the immune system, metabolism and the brain.